102
drug disposition and pharmacodynamics. Causes of variations in drug metabolism
include the following:
- Individual factors such as age, sex, body fat and body weight
- Environmental factors such as pollutants, alcohol and smoking
- Physiological factors: e.g. function of liver, kidneys, lungs, and cardiovascular
system. - Genetic factors such as polymorphisms of drug metabolizing enzymes, drug
transporters, drug receptors, ion channels and signal transduction pathways - Concomitant drugs
- Concomitant diseases
Potential consequences of polymorphic drug metabolism are:- Prolongation or intensifi cation of pharmacological effect
- Adverse drug reactions
- Lack of prodrug activation
- Drug toxicity
- Lack of effi cacy at prescribed dose requiring increase in dosage
- Metabolism by alternative, deleterious pathways
- Drug-drug interactions
It is of considerable importance to know the metabolic status of an individual,
particularly when using drugs with a narrow therapeutic range. Differences in
metabolism of drugs can lead to severe toxicity or therapeutic failure by altering the
relation between dose and blood concentration of the pharmacologically active
drug. Inter- and intra-individual variability in pharmacokinetics of most drugs is
largely determined by variable liver function as described by parameters of hepatic
blood fl ow and metabolic capacity. Among the factors affecting these parameters
are genetic differences in metabolizing enzymes. Glucose-6-phosphate dehydroge-
nase and N-Acetyltransferase were the earliest enzymes to be studied. Currently the
most important of these are liver enzymes.
Enzymes Relevant to Drug Metabolism
There are more than 30 families of drug-metabolizing enzymes in humans and
essentially all have genetic variants, many of which translate into functional changes
in the proteins encoded. For practical purposes these enzymes can be divided into
phase I and phase II as shown in Table 4.1 :
Overall, in poor metabolizers, whether phase I or phase II, there is limited metab-
olism in most patients unless another major metabolic pathway involving other
enzymes exists. Drug metabolism also depends on whether the parent compound is
a prodrug that forms an active metabolite, and poor metabolizers under this condi-
tion will form only trace amounts of an active compound.